Disclosure: Dr. Mathew receives research support from the General Clinical Research Center, the National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health. Dr. Mathew has been named as an inventor on a use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the Food and Drug Administration for this indication, Dr. Mathew could benefit financially.

Dr. Mathew is assistant professor of Psychiatry at the Mount Sinai School of Medicine (MSSM) in New York City. A board-certified psychiatrist, Dr. Mathew is also attending physician in the Mood and Anxiety Disorders Program at the Mount Sinai Medical Center. In 2007, he received the American Foundation for Suicide Prevention Pfizer Travel Award as well as the Lamport Research Award from MSSM. In addition to therapeutic approaches for treatment-resistant depression and anxiety, Dr. Mathew’s research involves magnetic resonance imaging and spectroscopy applications to anxiety and mood disorders.

What is the basis for the undertaking of this research?

There has been approximately 30 years of research looking at ketamine as a probe for glutamate function and as a possible pharmacologic model for psychosis. In the early 1990s, John Krystal, MD, and several others discovered that ketamine can model the acute positive symptoms, negative symptoms, and cognitive disruptions observed in schizophrenia.1-3 As a result, injecting healthy volunteers with ketamine and having them perform a variety of cognitive tasks was believed to reflect schizophrenic pathology better than amphetamine-induced psychoses.

In the late 1990s, an attempt was made to further understand the ketamine response in major depressive disorder (MDD). At that time, studying patients with MDD was thought to expand understanding of the N-methyl-D-aspartate (NMDA) receptor hypofunction.

How does NMDA relate to the monoamine neurotransmitters in antidepressants?

Glutamate receptors can classified as ionotropic receptors, and NMDA is one of them. There are other ionotropic receptors, including kainate and a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA). Ionotropic receptors mediate fast receptor transmission and use-dependent changes required for brain plasticity. They are important for a host of normal functions such as cognition and learning.

It has been challenging to identify pharmacologic targets that do not result in seizure, stroke, or other sequelae of NMDA overactivity. However, newer drugs and approaches (eg, ketamine) have shown to be interesting and useful because NMDA and glutamate are found in 85% of circuits in the central nervous system (CNS). However, identifying subtype-selective and safe ligands of this system has been difficult. Glutamate is a ubiquitous system, but with its ubiquity comes the risk of overtoxicity.

What attracted people to ketamine?

Ketamine binds at the site of the NMDA receptor similarly to phencyclidine. Physicians are attracted to ketamine for numerous reasons. In psychiatric research, it was a good model for understanding glutamate and the NMDA receptor relevant to schizophrenia. In the 1960s, the drug was used for anesthetic purposes primarily in children. However, it was used in adults undergoing orthopedic procedures and in the field of gynecology as well. In addition, that ketamine is neither associated with significant side effects nor known to have a short half-life contributes to its popularity.

Was a psychiatric therapeutic response observed when ketamine was used as an anesthetic?

Yes. The doses were approximately 4–5 times higher than the current doses used to manage MDD. The most notable symptoms were emergence type reactions of dissociation, particularly in children emerging from the anesthesia. Ketamine was not systematically tracked to their mood, and that they were feeling better within the next 1–3 days was not systematically described. There have been reports in the pain literature that patients given ketamine for chronic refractory pain syndromes (eg, cancer-related pain) felt better in terms of their mood. However, tracking them long term for changes in depressive symptoms had not been conducted.

Is there a connection between the glutamate system and monoamine neurotransmitters?

Connections are directly observed in both animal models and human imaging models. For example, selective serotonin reuptake inhibitors (SSRIs) used in depression, anxiety, and obsessive-compuslive disorder (OCD) have been found to decrease glutamate regulation in specific areas.

Rosenberg and colleagues4 looked at glutamate signaling in caudate. They found overactivity in OCD and a down-modulation with subsequent SSRI treatment. The results showed that SSRIs and other serotonergic drugs could dampen overactivity of glutamate.

Conversely, γ-aminobutyric acid (GABA) is the major inhibitory amino acid that counterbalances some of the glutamatergic overactivity. SSRIs have been found to increase GABA.5 It is possible that established monoaminergic treatments work in both respects by decreasing overactivity and increasing the underactive GABA. In animal models, numerous examples show the connections between serotonin postsynaptic receptors (eg, 5-HT2A receptor) and specific components of the glutamate system.

Which drugs are major topics in research?

Of the Food and Drug Administration’s currently available drugs, investigators have been interested in acamprosate, lamotrigine, memantine, riluzole, and topiramate.

Riluzole is the only treatment approved for Lou Gehrig’s disease. It is a glutamate-release inhibitor that is believed to have AMPA receptor activity as well as the capability of increasing the reuptake into glial cells; the net effect could be neuroprotection. Topiramate is a well-described anticonvulsant with AMPA kainate receptor activity. The antiviral, amantadine, has been found to have weak NMDA activity, meaning it is a partial NMDA antagonist. Memantine, which is approved for Alzheimer’s disease, is an NMDA antagonist, but it is a lower affinity than ketamine. Acamprosate is believed to have glutamate activity. It works on the metabotropic glutamate (mGlu) receptor system as an antagonist. Lamotrigine, possibly the best-described drug for bipolar depression, has shown evidence of anti-glutamatergic activity.

Have the preliminary reports of D-cycloserine shown a pharmacologic spectrum different from other drugs in theory?

D-cycloserine is a partial NMDA agonist that works at the D-serine site on the NMDA channel. The theoretical rationale behind D-cycloserine is not an excitotoxicity neuroplasticity model, but an enhancement of extinction learning model. By itself, D-cycloserine does not appear to be anxiolytic or antidepressant. However, in conjunction with active forms of learning and extinction type psychotherapies (eg, prolonged exposure to social anxiety disorder, acrophobia, or height phobia), D-cycloserine co-administration results in more rapid improvements, particularly in extinguishing the stressor or the fear. The theory behind D-cycloserine capitalizes on the mechanisms of extinction learning as opposed to decreasing excitotoxicity and enhancing resilience.

Which FDA-approved drugs look most promising for clinical use?

The FDA-approved drug with the most momentum in terms of the data in treatment-resistant depression (TRD) is riluzole. At least two open-label studies in TRD involved patients who had not responded to ≥2 standard antidepressants.6,7 The National Institute of Mental Health (NIMH) is reviewing a grant that will determine whether or not there is a role for riluzole adjunctive therapy in unipolar depression.

A small study by Zarate and colleagues8 showed memantine to have negative effects in unipolar depression. However, there is still much interest in memantine, as this study involved a relatively small sample size and efficacy with dosing >20 milligrams was not measured. While acamprosate is being explored for off-label uses in depression and anxiety, ketamine is being looked at as an experimental model for acute treatment of depression. Ketamine is not being studied for its long-term potential outside of the hospital setting, but those studies are going to be ongoing.

Which patients would benefit from these treatments?

It is premature to discuss who would benefit from ketamine at this time as the numbers treated are extremely low. Further controlled investigations are necessary. Work is ongoing to uncover moderators and mediators of response to intravenous ketamine and similar approaches

In addition, the pilot data9 suggests that anxious and depressive patients would benefit from glutamate-modulating agents. According to results from the Sequenced Treatment Alternatives to Relieve Depression study,10 anxious depression is a risk factor for resistance and nonresponse to citalopram as well as augmentation strategies.

There is open-label evidence of efficacy of riluzole in OCD; however, there is no placebo-controlled data at this time.11,12
Topiramate has successfully treated patients for self-mutilation in OCD and borderline personality disorder, possibly due to topiramate’s benefits in the spectrum of compulsive-impulsive disorders (eg, binge eating disorder).

What are the risks associated with the use of these drugs?

The acute risks with intravenous infusion of ketamine include dissociation, described as having a sense of altered time, feeling light, or feeling outside a person’s body. These side effects tend to be transient and time limited. The patients we have studied have not had side effects beyond 2 hours following intravenous infusion.

There are some reports in the literature of frank psychosis and auditory hallucinations,13 but with the dose given (ie, approximately 25% the anesthetic dose), neither auditory nor visual hallucinations were seen. However, this is still something of which to be aware. As there are transient increases in blood pressure, patients with uncontrolled hypertension are not recommended for the treatment. In addition, this medication is given by anesthesia, meaning there is potential aspiration risk. Therefore, patients with inadequately treated gastroesophageal reflux disease are excluded.

Are neurokinin (NK)1 antagonists and corticotropin-releasing factor (CRF) antagonists moving ahead in as promising a way as glutamate?

Mount Sinai Medical Center is investigating both of those compounds. The NK1 receptor antagonist is being looked at in posttraumatic stress disorder (PTSD). The rationale pre-clinically and clinically is that substance P, which is a stress-related neuropeptide, is elevated in the cerebrospinal fluid of veterans with PTSD, and NK1 receptor activity has been co-localized in regions important in stress. The NK1 receptor is an attractive target in that it is a stress-related neuropeptide implicated in fear and anxiety as well as mood circuitry. Numerous companies have developed NK1 antagonists and are now hitting Phase II and even Phase III studies.14 CRF has been in the news and on the horizon for >10 years. A CRF-1 selective antagonist for the treatment of PTSD is being investigated, and numerous studies have examined this mechanism in patients with anxiety and depressive disorders.15 Although NK1 and CRF antagonists have been heavily considered, it has been difficult to have one of these drugs receive FDA approval. In fact, a Phase II study of a selective CRH-1 antagonist was just published and found lack of efficacy of this agent for major depression.16

Have other drugs been developed that are more practical in terms of administration or safety?

There has been a lot of interest in an experimental MGlu receptor agonist drug called LY2140023. In a recently published study, the drug performed better than placebo and was as effective as olanzapine, suggesting that LY2140023 has antipsychotic properties. This may have several implications in terms of new directions in schizophrenia and psychosis. Drugs similar to mGlu drugs have preclinical and clinical evidence of utility in depressive and anxiety disorders.

In terms of ease of use and safety, only time will tell. The preclinical safety data for one of the compounds was not favorable, and that development was halted due to seizures. However, more clinical testing needs to be conducted.

Do you expect any major study results on these drugs to be published or presented in the near future?

The mGlu family has numerous exciting and interesting compounds one should expect to hear about next year. In addition, ampakines, which are AMPA receptor potentiators, are being studied for cognitive deficits in schizophrenia, memory disorders, and MDD. One should also expect to hear about NMDA receptor 2B antagonists, which are subtype selective NMDA receptor antagonists, as Zarate and colleagues are performing studies on them at the NIMH.

Is there a number at Mount Sinai Medical Center to which anyone interested in exploring participation or referring a patient should call?

If anyone is interested, they can call 212-241-4480, and we would be happy to discuss any of the specifics of participation.

Is there anything you would like to add?

Although there is a lot of excitement about ketamine and the rapidity of onset, the NIMH has recently funded us to perform a definitive clinical trial comparing ketamine to an active control, as that has not been done to date. At this point, it is important to not go beyond the data and suggest ketamine is appropriate for treatment. Caution should be taken until more data emerges. PP